Role of

CDK 4/6 INHIBITOR

in Advance Breast Cancer

Indra Wijaya
FK UNPAD – RSHS BANDUNG
2021
Disclosure Statements

• Speaker honorarium from Zuellig Pharma Indonesia.

• No financial or nonfinancial relationship with the products in this

presentation.

• These materials are for educational sharing purpose only and are not
intended for promotional use.

• Slide credit: clinicaloptions.com

Objectives

• Review role of CDK4/6 in mediating endocrine resistance in BC

• Pharmacology of CDK4/6 inhibitors
• Landmark trials of CDK4/6 inhibitors
• Monitoring of side effects of CDK4/6 inhibitors
• Summary
BREAST CANCER SUBTYPES
TRIPLE
Subtype Luminal A Luminal B HER2 +
NEGATIVE
% of breast
40% 20% 10 – 15% 15 – 20%
cancer
ER + PR + ER + PR + HER2 + ER – PR – HER2 –
Phenotype Low Ki67 High Ki67
Proliferation
(GEP)

Histologic grade Low grade High grade

Treatment Endocrine Anti Her2 Chemotherapy

Therapy
Prognosis
Good Poor

GEP: gene expression phenotypes,

ER: estrogen receptor, PR: progesterone receptor Adapted from Ross et al. Oncologist. 2003;8(4):307-25.
Management of Advanced Breast Cancer

Objective treatments
ABC is currently incurable
• Palliative symptoms
• Prolong survival while maintaining a good quality of life

Treatment considerations

Patients: Disease: Agents:

Menopausal status Tumor burden Mechanism of action
Organ function Rate of disease progression Expected toxicity
Comorbidities Prior therapy
Sites and extent of disease
Adherence, compliance Pharmacological interactions
Expression of hormonal receptors
Expectations and preferences Availability
Length of disease-free interval
Cost
Predictive biomarkers
Presence of gBRCA1/2 mutation

Matutino. Curr Oncol. 2018;25:S131. Rugo. JCO. 2016;34:3069.

Initial Treatment of HR+/HER2-
Advanced Breast Cancer
• Majority of patients with
HR+/HER2- MBC should be
treated with serial endocrine
therapy–based regimens
generally in combination with
targeted therapies
• Chemotherapy is not
recommended for HR+/HER2-
MBC unless patients’ cancer has
progressed through multiple lines of
endocrine therapy or patients
display signs of visceral crisis.
Matutino. Curr Oncol. 2018;25:S131.
Rugo. JCO. 2016;34:3069.
VISCERAL CRISIS is defined as severe organ
dysfunction as assessed by signs and symptoms,
laboratory studies, and rapid progression of disease.
Visceral crisis is not the mere presence of visceral
metastases but implies important ORGAN
compromise leading to a clinical indication for the
most rapidly efficacious therapy.
Examples:
• Liver visceral crisis: rapidly increasing bilirubin
>1.5x ULN
• Lung visceral crisis: rapidly increasing dyspnea
at rest, not alleviated by drainage of pleural
effusion
5th ESO-ESMO (ABC 5)
Ann Oncol.2020 Dec;31(12):1623-1649.
 Primary versus Secondary
E N D O C R I N E R E S I S TA N C E

 ET is the mainstay treatment of ER+ breast cancer, with 50-60% respond to first line ET.
 How to improve efficacy of endocrine therapy and delay onset of resistance?

5th ESO-ESMO (ABC 5)

Ann Oncol.2020 Dec;31(12):1623-1649.
Pathways Associated With ET Resistance In Vitro

Hoskins JM,. Et al. Nat Rev Cancer 9; 631-43.2009

Uncovering Mechanisms of
Endocrine Therapy Resistance

1. Upregulation of cell cycle

pathways
- CDK 4/6 pathway
2. Activation of signaling
pathways
- PI3K /Akt/mTOR pathway
3. Deregulation of ER
- ESR1 activating mutations
4. Inhibition of growth factor
receptor pathways.
5. Epigenetic modifications
Mechanisms of resistance may include loss/alteration of ER expression;
overexpression/activation of GF receptors; or activation of downstream
signal transduction pathways

Brufsky. Oncologist. 2018;23:528. AlFakeeh. Curr Oncol. 2018;25:S18.

C. Maureret al. / The Breast 34 (2017), 1-11
Evolving Treatment Landscape of HR+ Advanced MBC

McAndrew N, et al, Onco Hem Rev (US). 2020;16(1):23–9

Cyclin D–CDK4/6 Is Implicated in Crosstalk between
ER, HER2, and CDK4/6
Breast Cancer Tumorigenesis
• Diverse signaling pathways converge at cyclin D to drive
cell proliferation.
• Nuclear hormone, PI3K/AKT/mTOR, MAPK, Wnt/β-catenin,
JAK-STAT, and NF-κB pathways..
• The PI3K/AKT/mTOR pathway is activated in 77%.

• Mitogenic signaling through ER and HER2 requires cyclin D1

• Cyclin D1 is a direct ER-target gene that is required for
estrogen-dependent cell proliferation .
• Cyclin D1-deficient mice are resistant to HER2-induced BCs .
• ER+/HER2+ cell lines are most sensitive to CDK4/6 inhibition .

• Cyclin D–CDK4/6–INK4–Rb pathway is also disrupted through:

• CCND1 (cyclin D1) amplification – 35%
• CDK4 amplification – 16%.
• CDK6 amplification – 17%.
• Loss of p16 – 49%.
• Inactivating alterations of TP53 (p21 activator) – 84% of basal and 27% of non-basal tumors

• Cyclin D–CDK4/6–INK4–Rb pathway activation is associated with poor response of BC cells to

endocrine therapy, and CDK4/6 inhibition blocks cell-cycle progression in endocrine-resistant.

1. Lange CA, et al. Endocrine Relat Cancer 2011;18:C18–C24; 2. Witzel II, et al. Biochem Soc Trans 2010;38:217–222;
3. TCGA, Nature 2012;490:61–70; 4. Lukas J, et al. Mol Cell Biol 1996;16:6917–6925;
5. Prall OW, et al. J Steroid Biochem Mol Biol 1998;65:169-74; 6. Yu Q, et al. Nature 2001;411:1017–1021;
7. Finn RS, et al. Breast Cancer Res 2009;11:R77; 8. Geradts J, Wilson PA, Am J Pathol 1996:149:15–20;
9. Thangavel C, et al. Endocr Relat Cancer 2011;18:333–345.
 Regulation of G1/S checkpoint &
Mechanism of action of CDK4-6 Inhibitors

• (CDK4/6) inhibitors are small molecule

which are selective for CDK 4 and 6.

• CDKs have a role in regulating

progression through the cell cycle at the
G1/S phase by blocking retinoblastoma
(Rb) hyperphosphorylation.

• CDK4-6 inhibitors reduce proliferation of

breast cancer cell lines by preventing
progression from the G1 to the S cell
cycle phase.

Finn 2015; Sledge 2017; Hortobagyi 2016

 Selective CDK4/6 Inhibitors:
Three Drugs Have Been FDA Approved

February 2015 March 2017 September 2017

Ammazzalorso et at. Molecules. 2021, 26, 1488

 Clinical Pharmacology of CDK4-6 Inhibitors
CDK4/6i Palbociclib Ribociclib Abemaciclib
Absorption Increased with high-fat, high-calorie food ---- ------

Dosages Oral: 125 mg once daily for 21 Oral: 600 mg once daily for 21 150 mg twice daily + AI (first
days, followed by 7 days off, repeat days, followed by a 7-day rest line) or with Fulvestrant (2nd
every 28 days (in combination with period to complete a 28-day line) 200 mg twice daily (as a
continuous aromatase inhibitor treatment cycle (in combination single-agent)
therapy) with either an aromatase
inhibitor or fulvestrant)
Distribution Vd (mean): 2,583 L 1,090 L ~690.3 L; concentrations and active
metabolites in CSF are comparable
to unbound plasma concentrations
Protein binding ~85% ~70% 96%

Metabolism Extensively hepatic; primarily by CYP3A Extensively hepatic, predominantly Hepatic, predominantly via CYP3A4
and sulfotransferase (SULT) enzyme via CYP3A4
SULT2A1
Bioavailability 46% ------ 45%

Half-life elimination 29 ± 5 hours ~30 to 55 hours 18.3 hours

Time to peak 6 to 12 hours 1 to 4 hours 8 hours

Excretion: Faeces= 74% Urine= 18%; Faeces= 69% Urine= 23%; Faeces= 81% Urine= 3%;

Tzelepi et al., Forum of Clinical Oncology 2020. 10(2):2-14

Renal and Hepatic Dosing at initiation
CDK4-6 Palbociclib Ribociclib Abemaciclib
inhibitors
Renal Impairment CrCl >15 mL/minute: No adjustment CrCl= 30 to <90 mL/min: No CrCl >30 mL/minute: No
dosage adjustment adjustment
CrCl ≤15 mL/minute & HD: Not studied
CrCl= 15 to <30 mL/minute: CrCl ≤30 mL/minute & ESRD:
Reduce initial dose to 200 mg Not studied
daily based on a PK study in
subjects with no cancer

ESRD: Not studied

Hepatic impairment at Child-Pugh class A or B): No dosage Child-Pugh class A : No dosage Child-Pugh A or B: No dosage
treatment initiation: adjustment necessary. adjustment necessary. adjustment necessary.

(Child-Pugh class C): Reduce the dose to Child-Pugh B or C: Reduce the Child-Pugh class C: Reduce the
75 mg once daily. dose to 400 mg once daily. frequency to once daily.

Tzelepi et al., Forum of Clinical Oncology 2020. 10(2):2-14

Key Adverse Events With CDK4/6 Inhibitors:
Monitoring and Prevention

Diarrhea Hepatobiliary QT Prolongation Neutropenia VTE ILD/

Toxicity Pneumonitis

Abemaciclib Abemaciclib Abemaciclib Abemaciclib Abemaciclib

Palbociclib Palbociclib Palbociclib

Ribociclib Ribociclib Ribociclib Ribociclib Ribociclib

Antidiarrheal therapy LFTs before starting ECG before cycle 1, CBC before starting tx,
Monitor for signs Monitor for
tx, Q2W x 2 mo, Day 14 of cycle 1, then: and symptoms of pulmonary
Increase oral then: start of cycle 2, then thrombosis or symptoms indicative
 Abemaciclib, Q2W
hydration as indicated x 2 mo, QM x 2 pulmonary embolism of ILD or
 abemaciclib, as pneumonitis
mo, then as
Notify HCP indicated Electrolytes at start indicated (eg, hypoxia, cough,
 ribociclib, at start of cycle x 6 cycles,  Palbociclib, Days 1 dyspnea)
of cycle x 4 cycles then as indicated and 15 of cycles 1-
2, then as indicated
 Ribociclib, Q2W x
2 cycles, start of
next 4 cycles, then
as indicated

Abemaciclib PI. Palbociclib PI. Ribociclib PI.

Tzelepi et al., Forum of Clinical Oncology 2020. 10(2):2-14

Common grade 3–4 adverse events reported in pivotal trials
of CDK4/6 inhibitors

Antonio Marra A. npj Breast Cancer (2019) 5:27

Recommendation for Diarrhea Management

• A dose reduction corresponds to a reduction of 50 mg of abemaciclib at a time

• Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily
• For patients who have grade 4 diarrhea and continue to show the symptoms, even with dose reduction, should consult a doctor

Annals of Oncology (2018) 29 (suppl_8): viii90-viii 121.10.1093/annonc/mdy272

Dose Modifications
In Case of Neutropenia

• Blood counts should be performed before starting abemaciclib treatment, every 2 weeks for the first 2 months, monthly for the next 2 months, and as
clinically indicated.
• If blood cell growth factors are administered, abemaciclib treatment must be suspended for at least 48 hours after the last administration of the cell
growth factors and until toxicity resolves to Grade 2 or less. Resume at next lower dose unless the dose was already reduced for the toxicity that led to the
use of the growth factor.
• For patients who have grade 4 neutropenia and continue to show the symptoms, even with dose reduction, should consult a doctor.

Annals of Oncology (2018) 29 (suppl_8): viii90-viii 121.10.1093/annonc/mdy27

Dosing adjustment: Toxicity
Dose Level Abemaciclib + Abemaciclib Palbociclib Ribociclib
Fulvestrant or AI Monotherapy
Recommended 150 mg BID 200 mg BID 125 mg/day 600 mg/day
starting dose
First dose reduction 100 mg BID 150 mg BID 100 mg/day 400 mg/day
Second dose 50 mg BID 100 mg BID 75 mg/day 200 mg/day
reduction
Further dose Discontinue if further 50 mg BID Discontinue if further Discontinue if further
reductions dose reductions dose reductions dose reductions
needed beyond 50 mg needed beyond needed beyond
BID 75 mg/day 200 mg/day

• Abemaciclib, palbociclib, and ribociclib can be taken with or without food

• Medication should be taken at approximately the same time each day
• Avoid concomitant use of strong CYP3A4 inhibitors and inducers

Abemaciclib PI. Palbociclib PI. Ribociclib PI.

Clinical Efficacy of CDK4/6 Inhibitors
in 1st and 2nd line use
Clinical Efficacy of CDK4-6 inhibitors in 1 st line
Palbociclib Ribociclib Abemaciclib

PFS 24.8 m Vs PFS 25.3 m Vs 16 PFS 28.18 m Vs

14.5 m HR 0.58 m HR 0.568 14.7 m HR 0.465

PALOMA-2 Study, MONALEEZA-2 Study & MONARCH-3 Study

Clinical Efficacy of CDK4-6 inhibitors in 2nd line
Palbociclib Ribociclib Abemaciclib

PFS 9.2 m Vs 3.8 m PFS 20.5 m Vs PFS 16.4 m Vs 9.3 m

HR 0.42 12.8 m HR 0.59 HR 0.55

PALOMA-3 Study, MONALEEZA-3 Study & MONARCH-2 Study

 Systemic therapy for ER and/or PR positive
Recurrent Unresectable (Local or Regional) or stage IV (M1) disease
 ER positive / HER2 negative MBC
CDK4/6 Inhibitor

• A CDK4/6 inhibitor combined with endocrine therapy is the standard of care for
patients with ER+/HER-2 neg ABC, since it achieves substantial PFS benefit,
significantly increases OS and either maintains or improves QoL.

• The CDK4/6 inhibitor can be combined with an AI or with Fulvestrant, in de novo

or recurrent ABC, in 1st or 2nd line, and in cases of primary or secondary
resistance (as defined per ABC guidelines).

• This recommendation applies to post-menopausal women, to premenopausal

women in combination with an LHRH agonist, and to men preferably in
combination with an LHRH agonist.

5th ESO-ESMO (ABC 5)

LoE/GoE: I/A (97%) Ann Oncol.2020 Dec;31(12):1623-1649.
 ER positive / HER2 negative MBC
CDK4/6 Inhibitor
The ESMO-MCBS scores for the use of a CDK4/6 inhibitor combined with endocrine therapy for ABC
patients vary according to the setting and drug. They are the following, with the current available
data and FU:

• PALBOCICLIB + AI 1st line: Efficacy score: 3 (PFS); No improved QoL; ESMO-MCBS = 3

• ABEMACICLIB + AI 1st line: Efficacy score: 3 (PFS); No QoL reported; ESMO-MCBS = 3
• RIBOCICLIB + AI 1st line Post-menopausal: Efficacy score: 3 (PFS); No improved QoL; ESMO-MCBS : 3
• RIBOCICLIB + ET 1st line Pre-menopausal: Efficacy score: 4 (PFS&OS); Improved QoL; ESMO-MCBS : 5
• PALBOCICLIB + Fulvestrant 2nd line: Efficacy score: 3 (PFS&OS); Improved QoL; ESMO-MCBS : 4
• RIBOCICLIB + Fulvestrant (1st , 2nd line): Efficacy score: 4 (PFS&OS); No improvement in QoL; ESMO-MCBS = 4
• ABEMACICLIB + Fulvestrant 2nd line: Efficacy score: 4 (PFS&OS); No QoL benefit; ESMO-MCBS = 4

(LoE/GoR : I/A) (100%)

Of note, the three CDK4/6 inhibitors have not been compared head-to-head within a clinical trial.
In manuscript: MCBS scores will be updated when new data is available

5th ESO-ESMO (ABC 5)

LoE/GoE: I/A (97%) Ann Oncol.2020 Dec;31(12):1623-1649.
 CDK4/6i Is Active in Premenopausal Patients With MBC, Regardless of
Endocrine Therapy Partner

PALOMA-31 MONARCH-22 MONALEESA-73

• N = 108 • N = 114
• FULV + GnRH  N = 672
• FULV + goserelin
• Hazard ratio: 0.50; P = .013 • Hazard ratio: 0.45; P = .002  TAM* or NSAI+ goserelin
 Hazard ratio: 0.55; P = 1 x 10-9

Median PFS, Median PFS, Median PFS,

Mo Mo Mo
100 23.8
100 Palbociclib + FULV 9.5 Abemaciclib + FULV NR 100
Ribociclib + TAM/NSAI
Placebo + FULV 5.6 80 Placebo + FULV 10.5 Placebo + TAM/NSAI 13.0
80 PFS (%) 80
60

PFS (%)
PFS (%)

6 60
0 40
40 40
20 HR: 0.45
20 20
HR: 0.50 (95% CI: 0.29-0.87; P = .013) (95% CI: 0.264-0.754; P = .002) HR: 0.55 (95% CI: 0.44-0.69; P <.0001)
0 0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 4 8 12 16 20 2 28 0 2 4 6 8 10 12 14 16 18 2 2 24 2 28 30
Mo 4 Mo 0 2 6
Mo
*TAM should not be given with ribociclib due
to concerns about QT prolongation.[4]

Slide credit: clinicaloptions.com

1. Loibl. Oncologist. 2017;22:10283. 2. Neven. ASCO 2018. Abstr 1002. 3. Tripathy. Lancet Oncol. 2018;19:904.
4. Ribociclib PI. 5. Abemaciclib PI. 6. Palbociclib PI.
Are all CDK 4/6 inhibitors created equal?
Are all CDK 4/6 inhibitors created equal?

Ribociclib

Kai Yuan et al. https://doi.org/10.1016/j.apsb.2020.05.001

Progression-free survival (PFS) of CDK4/6 inhibitors in
clinical trials

Marra et al. npj Breast Cancer (2019) 5:27 ; https://doi.org/10.1038/s41523-019-0121-y

 Phase II Study: Abemaciclib in Patients With HR+ MBC and
Brain Metastases

 Received concomitant endocrine therapy Response, n N = 23

 Tumors previously treated with WBRT (%)
 Tumors previously treated with SRS
100
OIRR 2 (8.7)
CR
(95% CI: 0-20.2)
75 PR
SD CR 0
Change From Baseline (%)


50 PD
NE PR 2 (8.7)
25   SD 10 (43.5)
 
  
 SD ≥ 6 mos 2 (8.7)
0
PD or early 8 (34.8)
-25 
 death

CBR 4 (17.4)
-50 
 (95% CI: 1.9-32.9)
-75

-100 Individual Patients†

Tolaney. ASCO 2017. Abstr 1019. 6 patients not included due to lack of postbaseline tumor measurements.
†
Slide credit: clinicaloptions.com
Should CDK4/6 Inhibition Be Continued Beyond Progression? Not
Outside a Clinical Trial Setting!

Trial Agent Setting Phase N Endpoint Study Design

HR+/HER2- locally
MAINTAIN[1] Ribociclib advanced or MBC II 132 PFS at Fulvestrant + ribociclib vs
following progression WK 24 fulvestrant + placebo
on a CDK4/6 inhibitor

Endocrine pre-treated Fulvestrant vs fulvestrant

PACE[2] Palbociclib ER+/HER2- MBC; after II 220 PFS + palbociclib vs fulvestrant
CDK and endocrine + palbociclib +
therapy avelumab

HR+/HER2- locally Phase I:

advanced or MBC MTD Ribociclib + everolimus +
TRINITI-1[3,4] Ribociclib following progression I/II 107 exemestane
on a CDK4/6 inhibitor Phase II:
CBR

1. NCT02632045. 2. NCT03147287. 3. NCT02732119. 4. Bardia. ASCO 2019. Abstr 1016.

 Sequencing Therapy
Expert Considerations: Placement of CDK4/6i Therapy

• P13K Kinase activated: offer alpelisib after CDK4/6i, or

• Everolimus +ET in patients with P13K Kinase-WT or unknown
Summary
• Currently, the treatment landscapes for patients with advanced HR+ BC have changed:
delay and reduced use of chemotherapy.

• Combining CDK 4/6i + ET has change the management of HR+/HER2- metastatic breast
cancer
• Now the current standard of care.
• Combination regimens are better vs single agents.
• Statistically significant in clinical improvement in the 1L/2L setting of MBC:
• ORR, PFS, CBR, OS.
• Delay in time to chemotherapy.
• Improvements in PFS2.

• Abemaciclib, palbociclib and ribociclib had manageable side effect profiles; generally
well-tolerated.
Thank you
CDK4/6 inhibitors
in advanced breast cancer

@HOMBandung2021
Dosing adjustment: Toxicity
Palbociclib
May require treatment interruption/delay,
dose reduction, or discontinuation for
some adverse reactions.
Starting dose 125 mg once a day (in
combination with an aromatase inhibitor or
fulvestrant):
First dose reduction is to 100 mg daily;
Second reduction is required, reduce dose to
75 mg daily.
If unable to tolerate 75 mg daily ,
discontinue treatment.
Ribociclib
Recommended ribociclib dosage
adjustment levels:
Starting dose: 600 mg/day
First dose reduction: Reduce to 400
mg/day.
Second dose reduction: Reduce to 200
mg/day.
If unable to tolerate 200 mg twice
daily, discontinue ribociclib treatment
Tzelepi et al., Forum of Clinical Oncology 2020. 10(2):2-14
Abemaciclib
Starting dose 150 mg twice a day (in
combination with an aromatase
inhibitor or fulvestrant):
First dose reduction: Reduce
abemaciclib dose to 100 mg twice
daily.
Second dose reduction: Reduce
abemaciclib dose to 50 mg twice daily.
If unable to tolerate 50 mg twice daily,
discontinue abemaciclib treatment.
Can You Distinguish Between Agents?
Can You Switch Between CDK 4/6 Inhibitors?
Emerging Considerations
Ongoing Questions
Concluding Remarks
 Select Ongoing Trials With CDK4/6 Inhibitors in
HR+/HER2- EBC
Parameter ADAPTlate1,2 CARABELA3 eMonarchHER4 NATALEE5,6 POETIC-A7

Delayed extended Neoadjuvant

Treatment adjuvant abemaciclib + ET Adjuvant Adjuvant Adjuvant
abemaciclib vs AC-T abemaciclib + ET ribociclib + ET abemaciclib

Phase III II III III III

N 1250 200 2450 4000 2500

HR+, HER2-, HR+,HER2+, LN+

Patient HR+, HER2-, intermediate/ high-risk EBC HR+, HER2- EBC HR+, HER2-,
population high-risk EBC high-risk EBC high-risk EBC*

*Patients will be selected for endocrine resistance with preoperative aromatase inhibitor therapy.

1. Gluz. ASCO 2021. Abstr TPS598. 2. NCT04565054 3. NCT04293393. 4. Tolaney. ASCO 2021.
Abstr TPS596. 5. Slamon. ASCO 2019. Abstr TPS597. 6. NCT03701334 7. NCT04584853. Slide credit: clinicaloptions.com
Do CDK4/6 inhibitors result
in an improvement in OS?

YES
Slide credit: clinicaloptions.com
 Young-PEARL: Study Design
 Prospective, multicenter, open-label phase II study by the Korean Cancer Study
Group Stratified by prior cytotoxic CT for
MBC, presence of visceral mets

Palbociclib 125 mg QD x 3 wks +

Patients with premenopausal, Exemestane 25 mg QD x 4 wks +
inoperable, HR+*/HER2- MBC (or Leuprolide 3.75 mg SC Day 1 Q4W
locally advanced disease) who for 28-day cycles
received treatment with tamoxifen (n = 92)
and ≤ 1 line of CT for MBC; no
previous treatment with AI, CDK4/6 Capecitabine
inhibitor or capecitabine 1250 mg/m2 BID x 2 wks
(N = 184) for 21-day cycles
(n = 86†)
• Primary endpoint: PFS (investigator assessed)
• Secondary endpoint: DCR, OS, safety, QoL, biomarkers
*ER and/or PgR positive. †92 patients randomized, but 6 withdrew before receiving first dose of treatment.

Park. ASCO 2019. Abstr 1007.

 Young-PEARL: PFS (Investigator Assessed)
Median PFS,
100 Trial Arm Events, n Mos (95% CI)
Palbociclib/
exemestane/leuprolide 44 20.1 (14.2-21.8)
80
Capecitabine 47 14.4 (12.1-17.0)
60
PFS (%)

40

20
HR: 0.659 (95% CI: 0.437-0.994; P = .0469)
0
0 6 12 18 24 30
Palbociclib/ Mos
exemestane/leuprolide 92 89 85 82 74 59 49 38 28 16 10 5 2
Capecitabine 83 81 73 65 61 52 40 20 14 6 4 2 1

• Median follow-up: 17 mos

• Treatment ongoing in 47.8% of patients receiving palbociclib/exemestane/leuprolide, 39.5% of patients receiving capecitabine
Slide credit: clinicaloptions.com
Park. ASCO 2019. Abstr 1007.
 PEARL: Study Design
 International, randomized phase III study with 2 cohorts; 4 countries, 37 sites (GEICAM, CECOG)
‒ Cohort 1 recruited March 2014 to September 2016; cohort 2 recruited May 2016 to July 2018

Each cohort stratified by country, prior CT for MBC (Y/N), Exemestane 25 mg QD + Palbociclib 125 mg QD
prior sensitivity to HT (Y/N), presence of visceral mets 3 wks on/1 wk off
28-day cycles
(n = 153)
Patients with HR+/HER2- MBC, Cohort 1 (n = 296)
recurrence on or within 12 mos Capecitabine 1250 mg/m2 BID* 2 wks on/1 wk off Treatment until
of adjuvant NSAI, or progression 21-day cycles objective PD,
on or within 1 mo of NSAI (n = 143) symptomatic
therapy for advanced disease; deterioration,
≤ 1 line CT for MBC; Fulvestrant 500 mg Days 1, 15 of cycle 1, then once Q28D + toxicity, death, or
Palbociclib 125 mg QD 3 wks on/1 wk off
no previous capecitabine or withdrawal of
28-day cycles
exemestane/fulvestrant for (n = 149) consent
MBC Cohort 2 (n = 305)
(N = 601) Capecitabine 1250 mg/m2 BID* 2 wks on/1 wk off
21-day cycles
(n = 156)
*1000 mg/m2 BID if > 70 yrs of age.

ESR1 mutational ctDNA analysis done before treatment initiation. Martín. SABCS 2019. Abstr GS2-07.
PEARL: PFS
Comparison Median PFS, Mos HR P Value
(95% CI)

Cohort 2: FULV + PALBO (n = 149) vs CAPE (n = 156) 7.5 vs 10.0 1.09 .537
(0.83-1.44)

ESR1 WT: ET + PALBO (n = 206) vs CAPE (n = 187) 8.0 vs 10.6 1.08 .526
(0.85-1.36)

Cohorts 1 and 2: ET + PALBO (n = 302) vs CAPE (n = 299) 7.4 vs 9.4 1.09 .380
(0.90-1.31)

• 2 coprimary endpoints not met

• PFS with PALBO + FULV not superior to CAPE in patients with MBC resistant to AIs
• PFS with PALBO + ET not superior to CAPE in patients with ESR1 WT tumors

Martín. SABCS 2019. Abstr GS2-07.

Concluding Remarks
Sequencing Therapies
Additional Recommendations and Ongoing Studies
Sequencing Therapy Following Progression on
CDK 4/6i
Endocrine-Resistant ABC
Can CDK 4/6i Therapies Be Combined With an
AI?
Guidance and Treatment Options
Key Clinical Trials in Early BC
Biomarker Analysis in the Phase 3
MONALEESA Studies
Intrinsic Subtypes and Efficacy
Thank you
Role of
CDK4/6 inhibitors
in advanced breast cancer

@June2021
 Evolving Treatment Landscape of HR+ Advanced MBC

• SoC endocrine therapy regimens for HR+/HER2- MBC

Targeted Therapy + ET
Tamoxifen Fulvestrant
(selective ER (selective ER
modulator) degrader) Everolimus Ribociclib
(mTOR inhibitor) Abemaciclib
AIs (CDK4/6 inhibitors)
Anastrozole
Exemestane Palbociclib Alpelisib
Letrozole Fulvestrant HD (PI3Kα inhibitor)
(CDK4/6 inhibitor)

1970-80 1990s 2002 2010 2012 2015-17 2017-18 2019

FDA Approval
Anastrozole PI. Exemestane PI. Letrozole PI. Fulvestrant PI. Everolimus PI. Palbociclib PI. Ribociclib PI. Abemaciclib PI. Alpelisib PI. Brufsky.
Cancer Treat Rev. 2017;59:22. Lim E. Oncology (Williston Park). 2012;26:688. Croxtall. Drugs. 2011;71:363. Cohen. Oncologist. 2001;6:4.
Monitoring parameters
Palbociclib
CBC with differential (prior to
treatment initiation, every 2 weeks
for first 2 cycles, then prior to each
cycle, and as clinically indicated; if
neutropenia is limited to grades 1 or
2 in the first 6 cycles, monitor
every 3 months [prior to the
beginning of a cycle] and as
clinically indicated for subsequent
cycles).
Pregnancy test prior to treatment
initiation (in women of reproductive
potential);
Signs/symptoms of infection
Monitor adherence
Ribociclib
CBC with differential (baseline, every 2 weeks
for the first 2 cycles, at the beginning of each
subsequent 4 cycles and as clinically necessary).
LFTs (baseline, every 2 weeks for the first 2
cycles, at the beginning of each subsequent 4
cycles and as clinically necessary).
Serum electrolytes (K+, Mg++, Ca++, and
phosphorous) prior to treatment, at the
beginning of the first 6 cycles, and as clinically
indicated.
ECG (prior to treatment initiation; repeat on day
14 of cycle 1, at the beginning of cycle 2, and as
clinically indicated)
Pregnancy test prior to treatment (in females of
reproductive potential).
Monitor adherence.
Abemaciclib
CBC with differential and platelets
(at baseline, every 2 weeks for the
first 2 months, monthly for the next
2 months, then as clinically
indicated).
LFTs (at baseline, every 2 weeks
for the first 2 months, monthly for
the next 2 months, then as clinically
indicated).
Signs/symptoms of
diarrhea/dehydration and venous
thrombosis and pulmonary
embolism
pregnancy testing (prior to
treatment in females of reproductive
potential).
Monitor adherence.
63
 Adverse reactions of CDK4-6 Inhibitors
Palbociclib
Hematologic & oncologic:
Neutropenia grade 3: 56%;
grade 4: 10% to 12%
Anemia; grade 3: 3% to 6%, grade
4: <1%),
Leukopenia grade 3: 24% to 30%;
grade 4: 1%
Thrombocytopenia grade 3: 1% to
2%; grade 4: ≤1%
Gastrointestinal:
Nausea (34% to 35%), stomatitis
(28% to 30%), diarrhea (24% to
26%), vomiting (16% to 19%),
decreased appetite (15% to 16%)
Ribociclib
Hematologic & oncologic:
Neutropenia grade 3: 46% to 55%;
grade 4: 7% to 10%
Anemia; grade 3: 2% to 4%, grade 4: <1%),
Leukopenia grade 3: 12% to 20%; grade 4:
≤1%
Gastrointestinal:
Nausea (31% to 52%), diarrhea (29% to 35%),
Grade 3: 4%; vomiting (27% to 29%),
constipation (16% to 25%), decreased
appetite (16% to 19%), abdominal pain (11%
to 17%), stomatitis (10% to 12%; grade 3:
<1%)
Abemaciclib
Hematologic & oncologic:
Neutropenia grade 3: 19%;
grade 4: 5%
Anemia; grade 3: 5%
Leukopenia grade 3: 24% to 30%;
grade 4: 1%
Thrombocytopenia grade 3: 4%
Leukopenia grade 3: 5%; grade 4:
<1%
Gastrointestinal:
Diarrhea (90% grade 3: 13-20%),
nausea (64%), decreased appetite
(45%), abdominal pain (39%),
vomiting (35%), constipation
(17%), stomatitis (14%),
xerostomia (14%), dysgeusia (12%)
64

Adverse reactions of CDK4-6 Inhibitors
Palbociclib
Hepatic: Increased serum AST (8%
to 52%), increased serum ALT (6%
to 43%) Grade 4 ALT in 1 patient
only
Respiratory:
Epistaxis (7% to 9%)
CNS: Fatigue (37% to 41%)
Dermatologic: Alopecia (18% to
33%), skin rash (17% to 18%),
xeroderma (6% to 12%)
Infection: Infection (47% to 60%)
Neuromuscular & skeletal:
Weakness (8% to 17%)
Miscellaneous: Fever (12% to 13%)
65
Ribociclib Abemaciclib
Hepatic: Hepatic: Increased serum ALT
Elevation of AST (13% to 49%). ALT (13% to 46%), (31%), increased serum AST (30%)
abnormal LFTs (18%) Grade 3: ALT 4%, AST 2.3%
Grade ¾ ALT 8-9%, AST 5-6%
Respiratory: Respiratory:
Cough (15% to 22%), dyspnea (12% to 15%) Cough (19%)
CNS: Fatigue (37%), headache (22%), dizziness CNS: Fatigue (65%), headache
(13%), insomnia (12%) (20%), dizziness (11%)
Dermatologic: Alopecia (19% to 33%), skin rash Dermatologic: Alopecia (12%)
(17% to 23%), pruritus (10% to 20%)
Infection: Infection (47% to 60%) Infection: Infection (31%)
Neuromuscular & skeletal: Arthralgia (33%), back Neuromuscular & skeletal:
pain (20%), asthenia (12% to 14%) Arthralgia (15%)
Renal: Increased serum creatinine (20% to 65%) Renal: Increased serum creatinine
(13% to 98%)
Cardiovascular: Prolonged Q-T interval on ECG Miscellaneous: Fever (11%)
(1% to 6%), syncope (≤3%)
Miscellaneous: Fever (11% to 17%)
 Dosing adjustment: Hematologic toxicity:CTCAE V5
CDK4-6 Palbociclib
inhibitors
Grade 1 or 2 No dosage adjustment required
Grade 3 Day 1 of cycle: Withhold therapy and
repeat CBC with differential within 1 week.
When improved to ≤ grade 2, initiate the
next cycle at the same dose. Day 15 of first
2 cycles: If at grade 3, continue palbociclib
therapy at current dose to complete the
cycle. Repeat CBC with differential on day
22. If at grade 4 on day 22, withhold
palbociclib treatment until resolved to ≤
grade 2
Grade 3 (ANC Withhold treatment until resolved to ≤
500/mm3 to grade 2. Resume at next lower dose upon
<1,000/mm3) plus restarting.
fever ≥38.5°C
Grade 4 at any Withhold palbociclib treatment until
time resolved to ≤ grade 2. After resolution,
resume at next lower dose.
Ribociclib
No dosage adjustment
necessary.
Interrupt treatment until
recovery to grade 2 or lower
and then resume ribociclib at
the same dose. For recurrent
grade 3 neutropenia, interrupt
treatment until recovery and
then resume ribociclib at the
next lower dose level.
Interrupt treatment until
recovery to grade 2 or lower
and then resume ribociclib at
the next lower dose level.
Interrupt treatment until
recovery to grade 2 or lower
and then resume ribociclib at
the next lower dose level.
Abemaciclib
No abemaciclib dosage
adjustment necessary.
Withhold until toxicity
resolves to ≤ grade 2 (no
dosage reduction is
necessary)
-
Or recurrent grade 3;
Withhold abemaciclib until
toxicity resolves to ≤ grade 2
and then resume
abemaciclib at the next
lower dose.
66
 Hepatotoxicity during treatment: CTCAE V5

CDK4-6 Palbociclib Ribociclib Abemaciclib

inhibitors
Grade 1 (ALT ? No dosage Ribociclib adjustment necessary. No abemaciclib dosage adjustment
and/or AST necessary.
elevated >1 to 3
times ULN):
Grade 2 (ALT ? If baseline was below grade 2, interrupt treatment without increase in total bilirubin >2
and/or AST until recovery to baseline or lower and then resume times ULN: No abemaciclib dosage
elevated >3 to 5 ribociclib at the same dose level. For recurrent grade adjustment necessary.
times ULN) 2 elevations, interrupt treatment until recovery and
then resume ribociclib at the next lower dose level.
If baseline was at grade 2, no dosage adjustment
necessary.
Grade 3 (ALT ? Interrupt treatment until recovery to grade 2 or Interrupt treatment until recovery to
and/or AST lower and then resume ribociclib at the next lower grade 2 or lower and then resume
elevated >5 to 20 dose level. abemaciclib at the next lower dose
times ULN) level
Grade 4 (ALT ? OR Combined ALT and/or AST elevations >3 times OR Combined ALT and/or AST
and/or AST ULN with total bilirubin increase >2 times ULN: elevations >3 times ULN with total
elevated >20 times Discontinue ribociclib. bilirubin increase >2 times ULN:
ULN): Discontinue abemaciclib

67
 Non-hematology toxicity during treatment
Ribociclib
Cardiovascular: QT prolongation
QTcF >480 msec: Interrupt treatment; when QTcF resolves
to <481 msec, may resume ribociclib at the same dose
level.
If QTcF ≥481 msec recurs, interrupt treatment until QTcF
resolves to <481 msec and resume ribociclib at the next
lower dose level.
QTcF >500 msec: Interrupt treatment for QTcF >500 msec; if
QTcF resolves to <481 msec, may resume ribociclib at the
next lower dose level.
If QTcF interval prolongation is either >500 msec or >60
msec increase from baseline AND associated with torsades
de pointes, polymorphic ventricular tachycardia,
unexplained syncope, or signs/symptoms of serious
arrhythmia, permanently discontinue ribociclib.
Abemaciclib
Diarrhea
At the first sign of loose stools, begin management with
antidiarrheal agents and increase oral fluid intake
Grade 1: No abemaciclib dosage adjustment necessary.
Grade 2: If toxicity does not resolve to ≤ grade 1 within 24
hours, withhold abemaciclib until resolution (no abemaciclib
dosage reduction is necessary). Grade 2 that persists or
recurs after resumption at the same dose (despite maximal
supportive measures): Withhold abemaciclib until toxicity
resolves to ≤ grade 1 and then resume abemaciclib at the
next lower dose.
Grade 3 or 4 or requires hospitalization: Withhold
abemaciclib until toxicity resolves to ≤ grade 1 and then
resume abemaciclib at the next lower dose.
68
CDK4/6 and CANCER

CDK4 and CDK6 share very similar biochemical and

biological properties
 Impact of CDK4/6 Inhibition on PFS:
First-line Setting
Phase III PALOMA-2[1,2] MONALEESA-2[3,4] MONARCH-3[5,6] MONALEESA-3[7,8] MONALEESA-7[9]
Study
Setting 1st line 1st line 1st line 1st and 2nd line 1st line*
Endocrine Tamoxifen,
partner Letrozole
Letrozole Letrozole or anastrozole Fulvestrant letrozole, or
anastrozole
CDK4/6
inhibitor Palbociclib Ribociclib Abemaciclib Ribociclib Ribociclib

No. patients 666 668 493 365 672

HR 0.563 0.56 0.54 0.55 0.55
PFS, mos 27.6 vs 14.5 25.3 vs 16 28.18 vs 14.76 33.6 vs 19.2 23.8 vs 13.0
ORR, % 55.3 vs 44.4 52.7 vs 37.1 59 vs 44 40.9 vs 28.7† 41 vs 30
*1st line ET; up to 1 prior line of CT permitted in advanced setting (14% of patients had received CT in advanced setting). †Includes 1st and 2nd line.
1. Finn. NEJM. 2016;375:1925. 2. Rugo. Breast Cancer Res Treat. 2019;174:719. 3. Hortobagyi. NEJM. 2016;375:1738. 4. Hortobagyi.
Ann Oncol. 2018;29:1541. 5. Goetz. JCO. 2017;35:3638. 6. Johnston. NPJ Breast Cancer. 2019;5:5. 7. Slamon. JCO. 2018;36:2465.
8. Slamon. NEJM. 2020;382:514. 9. Tripathy. Lancet Oncol. 2018;19:904.
 MONALEESA-3: PFS by Line of
Therapy
• Median PFS for RIBO + FULV is now reached in first line: 33.6 mos

First Line Early Relapse + Second Line

RIBO + FULV PBO + FULV RIBO + FULV PBO + FULV
100 100
Events/N 112/237 95/128 Events/N 167/237 95/109
Median PFS, Median PFS, mos 14.6 9.1
33.6 19.2
80 mos 80
HR: 0.55 (95% CI: 0.42-0.72) HR: 0.57 (95% CI: 0.44-0.74)

60 60
RIBO + FULV
PFS (%)

40 40 RIBO + FULV
PBO + FULV
20 20
PBO + FUL

0 0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46
Mos Mos
Patients at Risk, n Patients at Risk, n
RIBO 237 204 187 178 171 164 157 147 140 132 125 123 117 113 102 101 98 84 63 44 20 7 2 0 RIBO 237 189 168 160 144 134 119 105 93 87 74 69 58 56 52 50 47 41 27 19 9 4 2 0
PBO 128 109 99 91 88 85 78 75 70 62 58 52 48 45 41 38 37 33 17 9 5 1 1 0 PBO 109 82 66 62 53 46 35 28 25 23 21 14 12 12 8 8 7 7 3 3 1 1 0 0

Slamon. NEJM. 2020;382:514. Slide credit: clinicaloptions.com

 PALOMA-2 and MONALEESA-2: PFS by Subgroup
PALOMA-2[1] MONALEESA-2[2]
Patients, n (%) Events, n/N
Subgroup Palbociclib + Placebo + HR Subgroup Ribociclib + Placebo + Favors Ribociclib Favors HR
Letrozole Letrozole (95% CI) Letrozole Letrozole + Letrozole Placebo + (95% CI)
Letrozole
All randomly assigned patients 444 (100) 222 (100) 0.58 (0.46-0.72) All patients 140/33 205/33 0.568 (0.457-0.704)
Age
< 65 yrs 263 (59.2) 141 (63.5) 0.57 (0.43-0.74) 4 4
≥ 65 yrs 181 (40.8) 81 (36.5) 0.57 (0.39-0.84) US patients 0.527 (0.351-0.793)
Race
White 344 (77.5) 172 (77.5) 0.58 (0.45-0.74) 38/100 63/113
Asian 65 (14.6) 30 (13.5) 0.48 (0.27-0.87) ECOG PS 0 0.581 (0.439-0.769)
Site of metastatic disease at 82/205 123/20
baseline 214 (48.2) 110 (49.5) 0.63 (0.47-0.85) 1 0.543 (0.385-0.766)
Visceral 230 (51.8) 112 (50.5) 0.50 (0.36-0.70) Age < 65 yrs 58/129 2 0.518 (0.392-0.684)
Nonvisceral
≥ 65 yrs 82/184 82/132 0.658 (0.466-0.928)
Prior hormonal therapy 249 (56.1) 126 (56.8) 0.53 (0.40-0.70)
Yes 195 (43.9) 96 (43.2) 0.63 (0.44-0.90) Race Asian 58/150 127/18 0.370 (0.180-0.760)
No
Non-Asian 14/28 9 0.614 (0.486-0.775)
Disease-free interval 167 (37.6) 81 (36.5) 0.67 (0.46-0.99)
Newly metastatic disease 99 (22.3) 48 (21.6) 0.50 (0.33-0.76) HR status ER+ and 121/28 78/145 0.606 (0.475-0.774)
≤ 12 mos 178 (40.1) 93 (41.9) 0.52 (0.36-0.73)
PgR+ 1 19/23
> 12 mos 171/28
Region 168 (37.8) 99 (44.6) 0.60 (0.43-0.85) Other 109/26 0.358 (0.217-0.591)
North America 212 (47.7) 95 (42.8) 0.57 (0.41-0.80) Liver or lung No 9 7 0.597 (0.426-0.837)
Europe 64 (14.4) 28 (12.6) 0.49 (0.27-0.87)
metastases Yes 162/27 0.561 (0.424-0.743)
Asia Pacific
ECOG PS 257 (57.9) 102 (45.9) 0.65 (0.47-0.90) 31/65 7
0 187 (42.1) 120 (54.1) 0.53 (0.39-0.72)
Bone-only No 59/152 0.551 (0.432-0.702)
1 or 2
disease 81/182 43/57 0.642 (0.393-1.048)
Bone-only disease at baseline 103 (23.2) 48 (21.6) 0.36 (0.22-0.59) Yes
Yes 341 (76.8) 174 (78.4) 0.65 (0.51-0.84) 80/143
No 125/19
Measurable disease 338 (76.1) 171 (77.0) 0.66 (0.52-0.85) de novo No 114/26 0.579 (0.447-0.749)
Yes 106 (23.9) 51 (23.0) 0.35 (0.22-0.57) disease 5 1 0.569 (0.384-0.843)
No Yes
Prior chemotherapy 213 (48.0) 109 (49.1) 0.53 (0.40-0.72)
26/69
Yes 231 (52.0) 113 (50.9) 0.61 (0.44-0.84) 159/25 0.430 (0.205-0.901)
Previous ETNSAI, others
No 97/220 6 0.516 (0.376-0.708)
Most recent therapy 91 (20.5) 44 (19.8) 0.55 (0.34-0.88) TAM and/or 46/78
Aromatase inhibitor 154 (34.7) 75 (33.8) 0.56 (0.39-0.80) EXE 43/114 0.651 (0.468-0.904)
Antiestrogen
No. of disease sites 138 (31.1) 66 (29.7) 0.51 (0.34-0.77) None
1 306 (68.9) 156 (70.3) 0.61 (0.47-0.79) 15/30 144/22 0.640 (0.470-0.871)
≥2 63/146 1 0.501 (0.368-0.681)
Histopathologic classification 356 (80.2) 184 (82.9) 0.59 (0.46-0.75) Previous No 61/113
Ductal carcinoma 68 (15.3) 30 (13.5) 0.46 (0.26-0.78) chemotherapy Yes 62/158
Lobular carcinoma
0.15 0.20 0.40 0.60 0.801.00 2.00 69/188 17/23
0.0625 0.125 0.25 0. 1 2 4 6 8
Palbociclib + Letrozole Better Placebo + Letrozole Better 71/146 102/14 HR5 (95% CI)
1. Finn. NEJM. 2016;375:1925. 2. Hortobagyi. Breast Cancer Res. 2018;20:123. 9 Slide credit: clinicaloptions.com
86/162

102/18
9
103/14
5
 MONARCH-3: PFS Subgroup
Analysis
Subgroup, n Abemaciclib + NSAI Placebo + NSAI HR (95% CI)
All patients 328 165 0.540 (0.418-0.698)
Metastatic site
Visceral 173 89 0.567 (0.407-0.789)
Bone only 69 40 0.565 (0.306-1.044)
Other 86 36 0.368 (0.219-0.619)
Endocrine therapy
Prior AI therapy 85 50 0.428 (0.260-0.705)
Other prior endocrine therapy 66 30 0.806 (0.473-1.375)
No prior endocrine therapy 177 85 0.503 (0.352-0.717)
Disease setting 0.471 (0.312-0.712)
De novo metastatic 135 61 0.579 (0.416-0.805)
Metastatic recurrent 182 99
NSAI at cycle 1 0.515 (0.301-0.882)
Anastrozole 62 36 0.547 (0.410-0.729)
Letrozole 264 126
Measurable disease 0.517 (0.392-0.681)
Yes 267 132 0.519 (0.267-1.009)
No 61 33
Number of organs at baseline 0.509 (0.356-0.727)
3+ 152 78 0.523 (0.311-0.881)
2 77 41 0.593 (0.359-0.981)
1 98 45
Age group 0.481 (0.346-0.667)
< 65 yrs 180 91 0.616 (0.413-0.918)
≥ 65 yrs 148 74
Geographical region 0.763 (0.422-1.381)
North America 60 30 0.636 (0.451-0.896)
Europe 166 93 0.326 (0.200-0.531)
Asia 102 42
Race 0.664 (0.481-0.918)
White 186 102 0.338 (0.210-0.544)
Asian 103 45
PgR status 0.410 (0.246-0.685)
Negative 70 36 0.589 (0.440-0.789)
Positive 255 127
ECOG PS 0.528 (0.353-0.790)
1 136 61 0.538 (0.389-0.746)
0 192 104

0.25 0.5 1 2
Johnston. NPJ Breast Cancer. 2019;5:5. Favors Abemaciclib Favors Placebo Slide credit: clinicaloptions.com
 Impact of CDK4/6 Inhibition on PFS:
Second-line Setting
Phase III Study PALOMA-3[1,2] MONARCH-2[3] MONALEESA-3[4,5]
Setting 2nd line 2nd line 1st and 2nd line
Endocrine partner Fulvestrant Fulvestrant Fulvestrant
CDK4/6 inhibitor Palbociclib Abemaciclib Ribociclib
No. patients 521 669 346
HR 0.50 0.536 0.57
PFS, mos 11.2 vs 4.6 16.9 vs 9.3 14.6 vs 9.1
ORR, % 25 vs 11 48.1 vs 21.3 32.4 vs 21.5*
Different Patient Populations
Any # prior ET Only 1 prior ET 0-1 prior ET
1 prior CT allowed No prior CT allowed No prior CT allowed
*ORR includes 1st- and 2nd-line patients.
1. Cristofanilli. Lancet Oncol 2016;17:425. 2. Turner. NEJM. 2018;379:1926.
3. Sledge. JAMA Oncol. 2020;6:116. 4. Slamon. JCO. 2018;36:2465. 5. Slamon. NEJM. 2020;382:514. Slide credit: clinicaloptions.com
 Relatively High ORR With CDK4/6
Inhibition
First-line Setting
Phase III PALOMA-2[1] MONALEESA-2[2] MONARCH-3[3] MONALEESA-3[4] MONALEESA-7[5]
Study
Setting 1st line 1st line 1st line 1st and 2nd line 1st line*
CDK4/6i Palbociclib Ribociclib Abemaciclib Ribociclib Ribociclib
ORR, % 55.3 vs 44.4 52.7 vs 37.1 59 vs 44 40.9 vs 28.7† 41 vs 30

Second-line Setting and Beyond

Phase III Study PALOMA-3[6] MONARCH-2[7] MONALEESA-3[4]
Setting 2nd line 2nd line 1st and 2nd line
CDK4/6i Palbociclib Abemaciclib Ribociclib
ORR, % 25 vs 11 48.1 vs 21.3 41 vs 30†
*1st line ET; up to 1 prior line of CT permitted in advanced setting (14% of patients had received CT in advanced setting). †Includes 1st and 2nd line.

1. Finn. NEJM. 2016;375:1925. 2. Hortobagyi. NEJM. 2016;375:1738. *ORR includes

3. Goetz. first and 2 nd line
JCO. 2017;35:3638. pts
4. Slamon. JCO. 2018;36:2465.
5. Tripathy. Lancet Oncol. 2018;19:904. 6. Cristofanilli. Lancet Oncol 2016;17:425. 7. Sledge. JAMA Oncol. 2020;6:116. Slide credit: clinicaloptions.com
 Should CDK4/6 Inhibition Be Continued Beyond
Progression? Not Outside a Clinical Trial Setting!

Trial Agent Setting Phase N Endpoint Study Design

HR+/HER2- locally
MAINTAIN[1] Ribociclib advanced or MBC II 132 PFS at Fulvestrant + ribociclib vs
following progression WK 24 fulvestrant + placebo
on a CDK4/6 inhibitor

Endocrine pre-treated Fulvestrant vs fulvestrant

PACE[2] Palbociclib ER+/HER2- MBC; after II 220 PFS + palbociclib vs fulvestrant
CDK and endocrine + palbociclib +
therapy avelumab

HR+/HER2- locally Phase I:

advanced or MBC MTD Ribociclib + everolimus +
TRINITI-1[3,4] Ribociclib following progression I/II 107 exemestane
on a CDK4/6 inhibitor Phase II:
CBR

1. NCT02632045. 2. NCT03147287. 3. NCT02732119. 4. Bardia. ASCO 2019. Abstr 1016. Slide credit: clinicaloptions.com
CDK4/6 Inhibitors vs Chemotherapy
Toxicity Monitoring and Management
 PALOMA-3: Effect on PFS of Dose
Reductions due to Neutropenia
1.0 No difference in PFS observed between patients
+ +
+ who had ≥ 1 dose reduction vs no dose reduction
+++ due to neutropenia
0.8 ++ ++
+ + +++ + +
Probability of PFS

++++ + +++++
++++
0.6 +++ + ++++
+++++ +++++
++++
+ ++
Median PFS, Mos ++
0.4
≥ 1 dose reduction 9.5 ++++++ ++ +
No dose reductions 9.5
0.2
HR: 0.87 (95% CI: 0.61-1.25;
2-sided log-rank P = .45)
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Patients at Risk, n Mos
≥ 1 dose reduction 100 98 88 85 79 78 63 62 33 31 8 6 2 2 1 0
No dose reductions 245 235 193 188 168 166 139 135 58 54 24 17 5 5 0

Verma. Oncologist. 2016;21:1165. Slide credit: clinicaloptions.com

 Adverse Events: Ribociclib
• QTc prolongation
• 11 patients (3.3%) in the MONALEESA-2: Letrozole +
Ribociclib (n = 334)
letrozole + ribociclib arm Adverse
Event, %
• Reversible and early Any Grade Grade 3 Grade 4

• 1 sudden cardiac death: grade 3 Neutropenia 74.3 49.7 9.6

hypokalemia and grade 2 QTc Nausea 51.5 2.4 0
prolongation Diarrhea 35.0 1.2 0
Anemia 18.6 0.9 0.3
Elevated ALT 15.6 7.5 1.8
Elevated AST 15.0 4.8 0.9

Hortobagyi. NEJM. 2016;375:1738.

 Adverse Events: Abemaciclib Abemaciclib + NSAI (n = 327) Placebo + NSAI (n = 161)
TRAE in ≥ 20% of Patients on
Abemaciclib Arm of MONARCH-3 All Grade Grade 2 Grade 3 Grade 4 All Grade Grade 2 Grade 3 Grade 4

Any 323 102 169 152

22 (6.7) 70 (43.5) 36 (22.4) 4 (2.5)
(98.8) (31.2) (51.7) (94.4)
Diarrhea 269
99 (30.3) 31 (9.5) 0 52 (32.3) 14 (8.7) 2 (1.2) 0
(82.3)
Neutropenia 143
53 (16.2) 72 (22.0) 6 (1.8) 3 (1.9) 1 (0.6) 1 (0.6) 1 (0.6)
(43.7)
Fatigue 135
59 (18.0) 6 (1.8) -- 54 (33.5) 21 (13.0) 0 --
(41.3)
Nausea 135
40 (12.2) 4 (1.2) -- 33 (20.5) 1 (0.6) 2 (1.2) --
(41.3)
Anemia 103
49 (15.0) 23 (7.0) 0 13 (8.1) 3 (1.9) 2 (1.2) 0
(31.5)
Abdominal pain 102
24 (7.3) 6 (1.8) -- 21 (13.0) 6 (3.7) 2 (1.2) --
(31.2)
Deaths due to AEs in MONARCH-3:
• Vomiting abemaciclib
99 (30.3) 28 (8.6) arm:5 lung
(1.5) infection
0 (n = 4), embolism2 (1.2)
21 (13.0) (n = 2), respiratory
4 (2.5) failure
0
(n = 2), cerebral ischemia (n = 1), cerebrovascular accident (n = 1), pneumonitis (n = 1); placebo arm: general
Alopecia 90 (27.5) 7 (2.1)
physical health deterioration (n = 1), sudden death (n =-- 1) -- 18 (11.2) 0 -- --
Decreased appetite 86 (26.3) 30 (9.2) 5 (1.5) 0 17 (10.6) 3 (1.9) 1 (0.6) 0
Leukopenia
Johnston. NPJ Breast Cancer. 2019;5:5. 72 (22.0) 31 (9.5) 27 (8.3) 1 (0.3) 4 (2.5) 1 (0.6) Slide credit:
0 clinicaloptions.com
1 (0.6)
Blood creatinine increased 67 (20.5) 25 (7.6) 6 (1.8) 1 (0.3) 7 (4.3) 1 (0.6) 0 0
 Management of Interstitial Lung
Disease/Pneumonitis
• Rate of ILD/pneumonitis with CDK4/6 inhibitors ranges from 1.0% to 3.3% in
registrational trials[1-3]
• Grade 3/4 AEs occurred in 0.1% to 0.6% of patients
• Patients should be counseled on importance of contacting healthcare provider in
case of dry cough with/without fever[1-3]
• Monitor regularly for pulmonary symptoms or radiologic changes indicative of
ILD or pneumonitis (eg, hypoxia, cough, dyspnea, interstitial infiltrates)[1-3]
• If pneumonitis suspected, interrupt therapy immediately
• Seek pulmonary consultation and consider early institution of corticosteroids[4]
• Permanently discontinue if recurrent symptomatic or severe ILD/pneumonitis

1. Abemaciclib PI. 2. Palbociclib PI. 3. Ribociclib PI. 4. Jazieh. Expert Rev Anticancer Ther. 2019;19:917. Slide credit: clinicaloptions.com
Utility of CDK 4 and 6 Inhibitors
HR-Positive, HER2-Negative BC
CDK 4 and 6 Inhibitors vs Single-Agent Endocrine
Therapy
PFS and OS Benefit
Unmet Need in High-Risk ER+ Breast
Cancer